The vasopressin-vasopressin receptor system is involved in two key homeostatic functions. A principal function of vasopressin is to regulate osmolality of the blood through the V2 receptor (V2R) found in the kidney. A second function of vasopressin is as a pressor agent which is mediated by the V1a receptor (V1aR) found on blood vessels.
Experimentation has been performed with a number of vasopressin receptor agonists and antagonists for use in the treatment of a variety of diseases. Lenz, et al., Gut, 1985, 26(12), 1385-1386; Lenz, et al., Gut, 1989, 30(1), 90-96; Russell, et al., N. Engl. J. Med., 2008, 358(9), 877-887; Fimiani, et al., Eur. J. Intern. Med., 2011, 22(6), 587-590; Cardenas, et al., J. Hepatol., 2012, 56(3), 571-578; Sanyal, et al., Gastroenterol., 2008, 134(5), 1360-1368.
Of particular clinical interest is the use of vasopressin agonists for their pressor activity in patients with hypovolemia or hypotension in order to elevate arterial pressure. A significant drawback of existing full vasopressin agonists for this use is the potential to induce severe vasoconstriction and tissue hypoperfusion when used at pharmacological doses. Gulberg, et al., Hepatol., 1999, 30(4), 870-875; Yefet, et al., Isr. Med. Assoc. J., 2011, 13(3), 180-181; Sanyal, et al., Gastroenterol., 2008, 134(5), 1360-1368. The narrow therapeutic index of these compounds has restricted their use to patients where the risk of tissue hypoperfusion is acceptable due to the severity of the underlying condition being treated.
The V2 receptor (V2R) is primarily found in the kidneys, in particular on the principal cells of the collecting ducts, where it is responsible for concentrating urine by reabsorbing water from the glomerular ultrafiltrate. This water retention can lead to hyponatremia if fluid intake is not restricted proportionately. The V2R is also found at extra-renal locations such as on endothelial cells where it appears to be responsible for a variety of effects, including release of von Willebrand factor and nitric oxide. The V1a receptor (V1aR) is primarily found on smooth muscle cells throughout the vasculature where it acts as a key regulator of vascular tone. The vasopressin analog, terlipressin, has been approved in some countries for the treatment of several cirrhotic complications (bleeding esophageal varices and type 1 hepatorenal syndrome) and has been used to demonstrate the utility of using vasoconstriction to treat other cirrhotic complications (spontaneous bacterial peritonitis, type-2 hepatorenal syndrome and post paracentesis circulatory dysfunction).
Cirrhosis of the liver is a common end stage of excessive alcohol consumption or of hepatitis. In about a third of cirrhosis patients, fluid builds up in the peritoneal cavity, and this is controlled by paracentesis. Complications of paracentesis include hypovolaemia and an undesirable fall in arterial blood pressure. These have traditionally been checked by infusion of human albumin, and more recently, terlipressin.
The development of portal hypertension as a consequence of cirrhosis is the key factor in the cardiovascular complications associated with end-stage liver disease. The liver has a normal hepatic venous pressure gradient (HVPG) of 1-5 mm Hg. An increase in HVPG is caused by active and passive increases in intrahepatic vascular resistance associated with the development of cirrhosis. This triggers a reflex splanchnic arteriolar vasodilation leading to increase in portal blood flow and further contributes to the increase in HVPG diagnosed as portal hypertension once it exceeds 12 mm Hg. This shift of the total blood volume towards the splanchnic circulation leads to a decrease in the effective blood volume (i.e., blood volume in the central portion of the cardiovascular system), which triggers reflex mechanisms aiming at increasing blood volume, essentially sodium and water retention mechanisms and vasoconstrictor mechanisms, further increasing the intensity of blood volume shift towards the splanchnic circulation which increases portal blood flow. Eventually, worsening vasoconstriction at the kidney starts reducing renal blood flow leading to either chronic (type II hepatorenal syndrome, HRS2) or acute renal failure (type I hepatorenal syndrome; HRS1) depending on the speed of deterioration. Both types of renal failure are very difficult to manage clinically (i.e., reversing excessive renal vasoconstriction) without worsening splanchnic vasodilation and portal hypertension.
Current medical management of the most severe cardiovascular complications of cirrhosis primarily relies on either vasoconstrictor therapy or albumin administration. Vasoconstrictor therapy targeted to specifically reduce splanchnic vasodilation without further deteriorating renal blood flow is the therapeutic intervention of choice. However, there is no current “gold standard” of care, as available vasoconstrictive agents tend to have significant liabilities, such as an ineffective degree of splanchnic vasoconstriction and/or excessive degree of extra-splanchnic vasoconstriction, too short a duration of action, or too narrow a therapeutic window. In European countries, the emerging standard of care for the treatment of HRS1 is administration of terlipressin. Other earlier, less severe complications of cirrhosis are often managed with albumin as a volume expander in the absence of a safe vasoconstrictor.
Terlipressin has been shown to be effective in treating HRS1 in a large-scale, randomized, placebo-controlled, blinded clinical trial (Orphan Therapeutics), providing proof of concept that vasoconstriction can be effective in treating renal failure in the context of cirrhosis (HRS1). Although the trial did not achieve its primary endpoint (survival with a reversal of HRS), terlipressin will likely become the therapeutic of choice for HRS1 in the regions of the world where it is approved. While terlipressin is considered better than fluid/albumin therapy alone, it is only able to reverse renal failure in 30-40% of patients, leaving room for improvement. Terlipressin has demonstrated clinical efficacy in bleeding esophageal varices (BEV) and HRS1, but it has drawbacks such as a relatively short duration of action when used at lower, and hence safer, doses, and too much extra-splanchnic vasoconstriction at higher doses. It is not practical to use terlipressin outside of a monitored, inpatient setting due to its need for frequent dosing (every 4-6 h or via IV infusion) and the potential for severe adverse events. While these severe adverse events are uncommon, they are potentially life threatening and must be managed accordingly.